CN103086863B - Alkannin dimer compounds and uses of the same in drug preparation - Google Patents
Alkannin dimer compounds and uses of the same in drug preparation Download PDFInfo
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- CN103086863B CN103086863B CN201110332078.XA CN201110332078A CN103086863B CN 103086863 B CN103086863 B CN 103086863B CN 201110332078 A CN201110332078 A CN 201110332078A CN 103086863 B CN103086863 B CN 103086863B
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Abstract
The present invention belongs to the field of drug preparation, and relates to alkannin dimer compounds and uses of the alkannin dimer compounds in anti-complements and anti-tumor drug preparation. According to the present invention, alkannin dimer compounds are extracted from an ethyl acetate position of a boraginaceae lithospermum plant Arnebia euchroma (Royle) Johnst, and activity evaluation tests confirm that strong inhibition effects and strong cytotoxic effects are provided for a classical pathway and an alternative pathway of a complement system, wherein CH50 of a complement system inhibition effect is 42+/-0.09-0.48+/-0.08 mM, AP50 is 0.14+/-0.01-0.19+/-0.03 mM, ED50 of a lung cancer cell (A549) inhibition effect is less than 0.32 mM, and the compounds can be used for preparation of anti-complements and anti-tumor drugs.
Description
Technical field
The invention belongs to field of traditional Chinese medicine pharmacy, relate to AK dimer compounds and the purposes in pharmacy thereof, especially in the purposes of preparing in anticomplement or antitumor drug.
Background technology
The excessive activation of complement system is understood the various diseases such as initiating system lupus erythematosus, rheumatoid arthritis, adult respiratory distress syndrome.At present this type of disease be there is no to desirable medicine, be therefore badly in need of clinically efficient, low toxicity, single-minded novel complement inhibitor.The cost of directly researching and developing complement inhibitor from natural product is low, and most of activeconstituentss can directly be digested and assimilated by body as a part for natural product, therefore from natural origin, find in recent years the new medicine with anticomplementary activity and be subject to people and more and more pay close attention to.Scholar both domestic and external separates and obtains a large amount of inhibiting monomeric compounds of complement system that have from natural product, for the research and development of anticomplement medicament provide wide prospect.
Tumour, especially malignant tumour, become one of principal disease of harm humans health in recent years.And traditional therapeutic modality is most taking single chemotherapy, radiotherapy and operation as main.Although these treatment plans have certain help for temporary transient elimination focus, but cannot reach all the time the object of radical cure tumour, how people contain aspect tumor growth has been done a large amount of research work, therefore from natural origin, finds in recent years the new medicine with anti-tumor activity and is subject to people and more and more pays close attention to.
Lithospermum euchromum Royle (Arnebia euchroma (Royle) Johnst) is the root of Boraginaceae (Boraginaceae) Lithospermum (Arnebia) plant, perennial herb, be distributed in the Southern Tianshan north slope in Xinjiang and the ground such as western part and siberian in Tibet, mountain gravel matter tailo, meadow and the grassy marshland etc. that grow in height above sea level 2500-4200 rice are located more.The root bitter of lithospermum euchromum Royle, cold in nature.There is the function of cooling and activating blood, clearing heat and detoxicating, laxation defaecation, can be used for preventing measles, pyreticosis macula, jaundice, purpura, tell nosebleed hematuria, blood pouring, bloody flux, carbuncle sore tumefacting virus, erysipelas, eczema, burn, constipation with heat retention.Modern pharmacological research confirms that it has the effects such as anti-inflammatory, antipyretic, analgesia, calmness, resisting pathogenic microbes, antitumor, antifertility.In recent years the research of Asian puccoon is concentrated in the separation and Structural Identification of chemical composition, therefrom separate and obtained the compounds such as some Shikonin classes, but there is not yet up to now AK dimer compounds and there is the report of anticomplement, anti-tumor activity.
Summary of the invention
The object of this invention is to provide the new material with anticomplementary activity, be specifically related to AK dimer compounds, be particularly related to the different AK A of compound (isoalkannin A) and different AK B (isoalkannin B) wherein, described compound is new compound.
A further object of the present invention is to provide the purposes of above-mentioned AK dimer compounds in pharmacy, especially in the purposes of preparing in anticomplement or antitumor drug.
The present invention's application modern pharmacology screening method, anticomplement, anti-tumor active substance in plant amedica are studied, separated and obtain AK dimer class active substance and confirm that it has anticomplement and antitumor action from the ethyl acetate extract of the ethanol extraction of Boraginaceae (Boraginaceae) Lithospermum (Arnebia) plant lithospermum euchromum Royle (Arnebia euchroma (Royle) Johnst) dry root.
AK dimer compounds of the present invention has the chemical structure of following formula:
Above-mentioned AK dimer compounds, in the time of R=H, compound is 7-(3-naphthoquinones base)-AK (different AK A, isoalkannin A); Work as R=CH
2cH=C (CH
3)
2time, compound is 3-isopentene group-7-(3-naphthoquinones base)-AK (different AK B, isoalkannin B).
Different alkannin compound of the present invention is prepared by following method:
Lithospermum euchromum Royle root meal 20kg, after under room temperature, with 95% ethanol, cold soaking, diacolation extract for several times repeatedly, decompression and solvent recovery, obtain medicinal extract 820g, medicinal extract is suspended in distilled water, with sherwood oil, ethyl acetate and n-butanol extraction, obtains acetic acid ethyl ester extract 420g.Get acetic acid ethyl ester extract 180g through silica gel column chromatography, with sherwood oil (60～90 DEG C), sherwood oil (60～90 DEG C)-acetone, acetone gradient elution, gained flow point carries out repeatedly silica gel column chromatography and preparative chromatography with different eluents, separation obtains compound 7-(3-naphthoquinones base)-AK (different AK A, isoalkannin A, 1) and 3-isopentene group, 7-(3-naphthoquinones base)-AK (different AK B, isoalkannin B, 2).
Wherein, 7-(3-naphthoquinones base)-AK (different AK A, isoalkannin A, 1): black amorphous powder, mp.112～114 DEG C,
=-87.2 (c 0.015mg/ml, acetone), UV (acetone): λ max:252,272,330,406,446,577nm.IR(KBr)v
max：3509～3000(br)，1685，1621，1384cm
-1。
1HNMR(400MHz，DMSO-d
6，ppm)：δ14.66(1H，s)，13.87(1H，s)，13.86(2H，s)，13.62(1H，s)，8.20(1H，s)，7.42(1H，s)，7.40(1H，d，J＝8.7Hz)，7.15(2H，s)，6.78(1H，d，J＝15Hz)，6.06(1H，d，J＝11.2Hz)，5.24(1H，t，J＝6.9Hz)，4.22(2H，d，J＝7.0Hz)，5.23(1H，t，J＝8.6Hz)，3.40(2H，m)，1.86(3H，s)，1.83(6H，s)，1.80(6H，s)，1.62(3H，s)。
13C NMR(100MHz，acetone-d
6，ppm)：δ186.9，186.2，183.4，183.2，165.8，156.2，155.8，155.7，154.8，142.9，140.2，135.8，130.4，130.2，127.1，127.0，126.9 126.4，125.1，125.0，123.1，121.7，115.3，115.2，114.5，113.4，79.1，56.1，26.3，26.1，25.7，18.6，18.5。
Wherein, 3-isopentene group, 7-(3-naphthoquinones base)-AK (different AK B, isoalkannin B, 2): black amorphous powder, mp.145～146 DEG C,
=-87.2 (c 0.015mg/ml, acetone), UV (acetone): λ max:252,272,330,406,446,577nm.IR(KBr)v
max：3509～3000(br)，1685，1621，1384cm
-1。
1H NMR(400MHz，acetone-d
6，ppm)：δ14.66(1H，s)，13.87(1H，s)，13.86(2H，s)，13.62(1H，s)，8.20(1H，s)，7.42(1H，s)，7.40(1H，d，J＝8.7Hz)，7.15(2H，s)，6.78(1H，d，J＝15Hz)，6.06(1H，d，J＝11.2Hz)，5.24(1H，t，J＝6.9Hz)，4.22(2H，d，J＝7.0Hz)，5.23(1H，t，J＝8.6Hz)，3.40(2H，m)，1.86(3H，s)，1.83(6H，s)，1.80(6H，s)，1.62(3H，s)。
13C NMR(100MHz，acetone-d
6，ppm)：δ188.0，187.7，185.1，185.0，165.8，158.3，157.6，157.5，157.1，154.7，142.3，142.3，140.4，135.2，130.7，128.9，127.6，127.4，126.6，124.3，123.1，120.1，116.6，116.5，116.5，115.6，114.9，69.9，33.7，27.3，26.0，25.9，23.3，20.2，18.5，18.0。
Above-mentioned AK dimer compounds is through external classical pathway and the confirmation of bypass anticomplementary activity shaker test result, and classical pathway and the alternative pathway of described compound to complement system all has remarkable restraining effect (as shown in table 1).Wherein, classical pathway and the alternative pathway of 3-isopentene group-7-(3-naphthoquinones base)-AK (different AK B, isoalkannin B, 2) to complement system all has strong restraining effect, and 50% suppresses the required trial-product concentration C of haemolysis H
50be 0.42 ± 0.09mM, AP
50be 0.14 ± 0.01mM.
Table 1 is that the different AK A-B of AK dimer compounds is to complement system classical pathway and the inhibiting data of alternative pathway.
The restraining effect of table 1 AK dimer compounds to complement system
aμg/ml。
AK dimer compounds of the present invention is through the confirmation of anti tumor activity in vitro shaker test result, and described compound has significant restraining effect to lung carcinoma cell (A549), to the inhibiting ED of lung carcinoma cell (A549)
50for < 0.32mM.
AK dimer compounds of the present invention can be used for preparing anticomplement and antitumor drug.
Brief description of the drawings:
Fig. 1 is the extraction separation process figure of AK dimer compounds different AK A～different AK B.
Embodiment
The preparation of embodiment 1 AK dimer compounds
Lithospermum euchromum Royle dry root 20kg, meal is after under room temperature, with 95% ethanol, cold soaking, diacolation extract for several times repeatedly, decompression and solvent recovery, obtain medicinal extract 820g, medicinal extract is suspended in distilled water, with sherwood oil, ethyl acetate and n-butanol extraction, obtains acetic acid ethyl ester extract 420g.Get acetic acid ethyl ester extract 180g, through silica gel column chromatography, obtain 7 stream part Fr.1～Fr.7 with sherwood oil (60～90 DEG C), sherwood oil (60～90 DEG C)-acetone gradient elution, Fr.6 is through silica gel column chromatography, taking sherwood oil-acetone (4: 1) as eluent, obtain 9 stream part Fr.6-1～Fr.6-9, gained stream part Fr6-6 is through preparative chromatography, taking chloroform-methanol (20: 1) as developping agent, obtain 1 (8mg); Fr.7 is through silica gel column chromatography, taking sherwood oil-acetone (2: 1) as eluent, obtain 4 stream part Fr.7-1～Fr.7-4, gained stream part Fr7-2 is through preparative chromatography, taking chloroform-methanol (15: 1) as developping agent, obtain 2 (4mg); Identify that through Wave Spectrum this compound 1-2 is the AK dimer compounds with new skeleton, respectively the different AK A of called after (isoalkannin A) and different AK B (isoalkannin B).
Embodiment 2 antitumor activity in vitro (srb assay)
A549 (people's lung cancer) tumor cell line in the T-25 flask of the 10% calf serum RPMI1640 nutrient solution 4ml containing 25mM HEPES, 0.2% (w/v) sodium bicarbonate and 100 μ g/ml kantlex, 37 DEG C, 5%CO
2condition under cultivate.Cell suspending liquid after tryptic digestion adds in 96 orifice plates, and cell concn is 0.25-1 × 10
4/ hole.Tumour cell adds the component to be measured of different concns to cultivate after 72 hours at 37 DEG C, fixes and uses (SRB) dyeing of 0.4% with 50% ice-cold trichoroacetic acid(TCA), after dyestuff dissolves, under 562nm, measures absorption value.Drug level ED when cell half growth-inhibiting
50convert according to dose-effect data.In triplicate, absorption value difference is less than 5%, ED in each experiment
50difference is less than 30%.
Embodiment 3 In Vitro Anti classical pathway of complement tests
Get complement (guinea pig serum) 0.1ml, add BBS to be mixed with 1: 5 solution, with BBS two-fold dilution become 1: 10,1: 20,1: 40,1: 80,1: 160,1: 320 and 1: 640 solution.Get 1: 1000 hemolysin, each concentration complement and the each 0.1ml of 2%SRBC and be dissolved in 0.3ml BBS, mix, after 37 DEG C of water-bath 30min, put into low-temperature and high-speed whizzer, centrifugal 10min under 5000rpm, 4 DEG C of conditions.Get respectively every pipe supernatant 0.2ml in 96 orifice plates, measure absorbancy at 405nm.Experiment arranges full haemolysis group (0.1ml 2%SRBC is dissolved in 0.5ml tri-distilled water) simultaneously.Using the absorbancy of tri-distilled water haemolysis pipe as full haemolysis standard, calculate hemolysis rate.Taking complement extent of dilution as X-axis, the percentage of hemolysis that each weaker concn complement causes is Y-axis mapping.Selection reaches the minimum complement concentration of similar high hemolysis rate as guaranteeing that system can the normal required critical complement concentration of haemolysis.Complement and the trial-product of getting threshold concentration mix, and after 37 DEG C of pre-water-bath 10min, add appropriate BBS, hemolysin and 2%SRBC.To after 37 DEG C of water-bath 30min of every pipe, put into low-temperature and high-speed whizzer, under 5000rpm, 4 DEG C of conditions, after centrifugal 10min, get respectively every pipe supernatant 0.2ml in 96 orifice plates, under 405nm, measure absorbancy.Experiment arranges trial-product control group, complement group and full haemolysis group simultaneously.After being deducted to corresponding trial-product control group absorbance, trial-product absorbance calculates hemolysis rate.Using trial-product concentration as X-axis, haemolysis inhibiting rate is mapped as Y-axis.Calculate CH
50value.
Embodiment 4 In Vitro Anti alternative pathway of complement tests
Get complement (human serum) 0.2ml, add AP diluent preparing to become 1: 5 diluting soln, and two-fold dilution becomes 1: 10,1: 20,1: 40,1: 80,1: 160,1: 320 and 1: 640 solution.Get each concentration complement 0.15ml, AP diluent 0.15ml and 0.5%RE 0.20ml, mix, after 37 DEG C of water-bath 30min, be placed into low-temperature and high-speed whizzer, centrifugal 10min under 5000rpm, 4 DEG C of conditions.Get respectively every pipe supernatant 0.2ml in 96 orifice plates, measure absorbancy at 405nm.Experiment arranges full haemolysis group (0.20ml 0.5%RE is dissolved in 0.3ml tri-distilled water) simultaneously.Using the absorbancy of tri-distilled water haemolysis pipe as full haemolysis standard, calculate hemolysis rate.Taking complement extent of dilution as X-axis, the percentage of hemolysis that each weaker concn complement causes is Y-axis mapping.Selection reaches the minimum complement concentration of similar high hemolysis rate as guaranteeing that system can the normal required critical complement concentration of haemolysis.Complement and the trial-product of getting definite threshold concentration mix, and after 37 DEG C of pre-water-bath 10min, add 0.2ml 0.5%RE.To after 37 DEG C of water-bath 30min of every pipe, be placed into low-temperature and high-speed whizzer, 5000rpm, 4 DEG C, gets respectively every pipe supernatant 0.2ml in 96 orifice plates after centrifugal 10min, measure its absorbancy under 405nm.Experiment arranges trial-product control group, complement group and full haemolysis group simultaneously.After being deducted to corresponding trial-product control group absorbance, trial-product absorbance calculates hemolysis rate.Using trial-product concentration as X-axis, haemolysis inhibiting rate is mapped as Y-axis, calculates AP
50value.
Claims (4)
1. there is the AK dimer compounds of following general structural formula,
R=H or CH
2cH=C (CH
3)
2.
2. AK dimer compounds claimed in claim 1 is in the purposes of preparing in anticomplement medicament.
3. AK dimer compounds claimed in claim 1 is in the purposes of preparing in antitumor drug.
4. by the purposes of claim 3, it is characterized in that, described tumour is lung cancer.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1374288A (en) * | 2002-03-19 | 2002-10-16 | 中山大学 | Gronwell naphthaquinone derivative and its application in preparing anticancer medicine |
| CN101597230A (en) * | 2009-07-03 | 2009-12-09 | 复旦大学 | β, beta-dimethyl-acry-lalkannin and the purposes in the preparation medicines for inhibiting drug-resistant bacteria |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1374288A (en) * | 2002-03-19 | 2002-10-16 | 中山大学 | Gronwell naphthaquinone derivative and its application in preparing anticancer medicine |
| CN101597230A (en) * | 2009-07-03 | 2009-12-09 | 复旦大学 | β, beta-dimethyl-acry-lalkannin and the purposes in the preparation medicines for inhibiting drug-resistant bacteria |
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